EP2985273B1 - Compound having cyclopropane ring, and flavor and/or fragance composition containing same - Google Patents

Compound having cyclopropane ring, and flavor and/or fragance composition containing same Download PDF

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EP2985273B1
EP2985273B1 EP14765462.8A EP14765462A EP2985273B1 EP 2985273 B1 EP2985273 B1 EP 2985273B1 EP 14765462 A EP14765462 A EP 14765462A EP 2985273 B1 EP2985273 B1 EP 2985273B1
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methyl
mmol
cdcl
mhz
minutes
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French (fr)
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EP2985273A1 (en
EP2985273A4 (en
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Kenichi Yamamoto
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Takasago International Corp
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Takasago International Corp
Takasago Perfumery Industry Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/34—Monohydroxylic alcohols containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/28—Saturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
    • C07C47/293—Saturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings with three- or four-membered ring
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A23L2/56—Flavouring or bittering agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/20—Synthetic spices, flavouring agents or condiments
    • A23L27/203—Alicyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/13—Monohydroxylic alcohols containing saturated rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/02—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen
    • C07C47/105—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/235—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B9/00—Essential oils; Perfumes
    • C11B9/0026—Essential oils; Perfumes compounds containing an alicyclic ring not condensed with another ring
    • C11B9/003—Essential oils; Perfumes compounds containing an alicyclic ring not condensed with another ring the ring containing less than six carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B9/00—Essential oils; Perfumes
    • C11B9/0061—Essential oils; Perfumes compounds containing a six-membered aromatic ring not condensed with another ring
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/005—Compositions containing perfumes; Compositions containing deodorants
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/10—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing oxygen
    • D06M13/12—Aldehydes; Ketones
    • D06M13/127—Mono-aldehydes, e.g. formaldehyde; Monoketones
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/10—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing oxygen
    • D06M13/144—Alcohols; Metal alcoholates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a flavor and/or fragrance composition containing a compound having a cyclopropane ring.
  • Some compounds having a cyclopropane ring are known to be useful as raw materials for flavor compositions and/or fragrance compositions.
  • [1-methyl-2-(5-methyl-4-hexen-2-yl)cyclopropyl]methanol has an odor similar to those of citrus and 3-methyl-5-phenyl-1-pentanol, with rosy floral note ( WO 2012/160189 A1 ).
  • 1-methyl-2-[(2,2,3-trimethylcyclopentyl)methyl]cyclopropyl] methanol has a natural sandalwood-like odor ( US 2010/0069508 A1 ).
  • 2-(1-phenylethyl)cyclopropylmethanol are known as compounds having a cyclopropane ring and a benzene ring, but their odors are not mentioned ( Synthesis (1999), No. 6, 1063-1075 ).
  • Secondary cis -isopropenylcyclopropylcarbinols have been obtained either by regio- and stereoselective hydroxyl-directed cyclopropanation of the corresponding dienols or from bicyclic cyclopropyl lactones derived from intramolecular cyclopropanation of allylic diazoacetates. Furthermore, it has been shown that base-induced 1,3-elimination of ⁇ -epoxy ketones afford trans -2-(hydroxymethyl)cyclopropyl ketones, and the reactivity of these compounds has been reinvestigated.
  • WO 2008/052379 A2 describes 2,2,3-trimethylcyclopentane derivatives of the following formula (1):
  • R 1 is methyl or ethyl
  • R 2 is hydrogen, methyl or ethyl.
  • WO 2008/052379 A2 furthermore relates to a method of the production of compounds of formula (1) and to fragrance compositions comprising same.
  • an object of the present invention is to provide a compound capable of imparting a floral or citrus-like odor satisfying the above-described requirements.
  • the present inventor has conducted intensive study, and consequently has found that a compound obtained by subjecting an allyl alcohol derivative to cyclopropane formation has a strong floral or citrus-like odor, and can serve as a useful odor-imparting agent. This finding has led to the completion of the present invention.
  • the present invention includes the following contents [1] to [7].
  • the compound of the present invention is a very useful flavor and/or fragrance material which is highly preferred, is also excellent in odor-imparting characteristics, and is excellent in diffusibility and long lasting.
  • an agent for imparting a highly preferred odor can be provided.
  • a compound of the present invention is represented by Formula (1):
  • R 1 and R 3 are both methyl groups
  • R 2 and R 5 each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • the alkyl group having 1 to 3 carbon atoms is, for example, a methyl group.
  • R 4 represents a group selected from a hydroxymethyl group, a 1-hydroxy-1-ethyl group, a 1-hydroxy-1-propyl group, a 1-hydroxy-1-butyl group, and a 2-hydroxy-1-propyl group.
  • R 4 is, for example, selected from a hydroxymethyl group, and a 1-hydroxy-1-ethyl group.
  • m is 0 to 2, and, for example, 0 or 1.
  • n is 0 or 1.
  • the wavy lines indicate a cis-configuration, a trans-configuration, or a mixture of a cis-configuration and a trans-configuration with respect to position-2 on the cyclopropane ring.
  • a compound of Formula (1), where n is 0, and R 4 is a hydroxymethyl group, is synthesized, for example, by a method shown below.
  • an allyl alcohol derivative (3) is reacted with a carbenoid prepared from diethylzinc and chloroiodomethane to synthesize a compound (4) having a cyclopropane ring.
  • the compound (4) having a cyclopropane ring is obtained as a mixture of diastereomers having the relative configurations shown below, and the odor threshold of (4b) is lower than that of (4a).
  • a compound of Formula (1), where n is 0, m is 0, R 1 and R 3 are methyl groups, and R 4 is a 1-hydroxy-1-ethyl group, is synthesized, for example, by a method shown below.
  • a compound (5) having a cyclopropane ring is oxidized to obtain an aldehyde compound (6), which is then subjected to a Grignard reaction.
  • a compound (7) can be synthesized.
  • Reactions usable as a method for the oxidation include the TEMPO oxidation, the Uemura Oxidation, the Albright-Goldman oxidation, the Mukaiyama oxidation, the Ley-Griffith oxidation, the Swern oxidation.
  • the compound (7) having a cyclopropane ring is obtained as a mixture of isomers having relative configurations shown below.
  • the odor threshold of (R*)-1-[(1S*,2S*)-1-methyl-2-((R*)-1-phenylethyl)cyclopropyl ]ethanol (7a) is 100 times or more lower than that of (S*)-1-[(1S*,2S*)-1-methyl-2-((R*)-1-phenylethyl)cyclopropyl ]ethanol (7b).
  • a compound having a cyclopropane ring of Formula (1), where n is 1, m is 0, R 1 and R 3 are methyl groups, and R 4 is a formyl group, is synthesized, for example, by a method shown below.
  • a compound (6) is subjected to the Wittig reaction to synthesize an enol ether (8).
  • the obtained enol ether is hydrolyzed in the presence of an acid catalyst.
  • an acid catalyst e.g., a compound (9) having a cyclopropane ring.
  • Acids used here include acetic acid, citric acid, hydrochloric acid, sulfuric acid.
  • the thus obtained compound of the present invention can be isolated and purified.
  • methods for the isolation and purification include column chromatography, vacuum distillation, crystallization. These methods can be carried out alone or in combination.
  • the amount of the compound represented by Formula (1) blended in a flavor and/or fragrance composition is not particularly limited, and is preferably 0.01 to 60% by weight, and particularly preferably 0.1 to 40% by weight, relative to the flavor and/or fragrance composition.
  • any commonly used blended flavor and/or fragrance can be blended in the flavor and/or fragrance composition of the present invention.
  • the thus obtained flavor and/or fragrance composition can impart a fresh and highly preferred odor.
  • the flavor and/or fragrance composition of the present invention can be blended, as an odor component, in foods and beverages, cosmetics, air-fresheners, daily necessities and groceries, oral cavity compositions, hair-care products, skin-care products, body-cleaning agents, laundry detergents, laundry softeners, toiletry products, fibers and fiber products, garments, pharmaceuticals.
  • the flavor and/or fragrance composition of the present invention can be blended in shampoos, rinses, perfumes, colognes, hair tonics, hair creams, pomades, base materials for other hair cosmetics, soaps, dish washing detergents, laundry detergents, softeners, sterilizing detergents, deodorant detergents, room air-fresheners, disinfectants, pesticides, bleaching agents, other various health and sanitary detergents, dentifrices, mouthwashes, toilet papers, odor-imparting agents for facilitating ingestion of pharmaceuticals, in amounts generally employed in these industrial fields. In this manner, its unique odor can be imparted to these products, and the values of the products can be enhanced.
  • GC/MS was measured by using an HP 6890 GC system and an HP5973MS detector of Agirent Technologies.
  • the column used was InertCap 1 (manufactured by GL Sciences Inc., 30 m in length ⁇ 0.25 mm in inner diameter, liquid-phase film thickness: 0.25 ⁇ m).
  • the injection port temperature was 250°C
  • the detector temperature was 250°C.
  • the conditions of the temperature rise were as follows: 100°C(15°C/minute)300°C.
  • the GC purity was measured by using a 7890A GC system of Agirent Technologies.
  • the column used was InertCap 1 (manufactured by GL Sciences Inc., 20 m in length ⁇ 0.18 in mm inner diameter, liquid-phase film thickness: 0.18 ⁇ m).
  • the injection port temperature was 250°C
  • the detector temperature was 250°C.
  • the conditions of the temperature rise were as follows: 100°C(15°C/minute)230°C.
  • a diethylzinc solution in toluene (concentration: 15% by weight, 37.9 g, 46.0 mmol) was placed into a 200-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -20°C.
  • Chloroiodomethane (16.22 g, 92.0 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 to -20°C. After completion of the dropwise addition, the mixture was stirred at -10 to -15°C for 30 minutes, and then cooled to -25°C.
  • a diethylzinc solution in toluene (concentration: 15% by weight, 69.8 g, 84.8 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -20°C.
  • Chloroiodomethane (29.9 g, 169.6 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -10 to -15°C for 30 minutes, and then cooled to -25°C.
  • aqueous sodium hypochlorite solution (concentration: approximately 13.5%, 5.0 g, 9.1 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept at 0°C. After completion of the dropwise addition, the temperature was raised to 18°C over a period of 60 minutes. After that, the aqueous layer was separated, and the organic layer was washed with a 10% aqueous sodium thiosulfate solution and with water. The solvent was recovered under reduced pressure to obtain a condensed residue, (1S*,2S*)-1-methyl-2-[(R*)-1-phenylethyl]cyclopropane carbaldehyde (0.91 g, 4.8 mmol, 89% yield).
  • methyl magnesium bromide (0.97 mol/L, tetrahydrofuran solution, 8.5 ml, 8.25 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -10°C.
  • (1S*,2S*)-1-Methyl-2-[(R*)-1-phenylethyl]cyclopropane carbaldehyde (1.03 g, 5.5 mmol) was placed into the dropping funnel, and added dropwise in 5 minutes with the temperature kept at -10°C. After stirring for 60 minutes, a 20% aqueous sulfuric acid solution (4.5 g) was added.
  • a diethylzinc solution in toluene (concentration: 15% by weight, 10.9 g, 13.2 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -15°C.
  • Chloroiodomethane (4.68 g, 26.5 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -15°C for 30 minutes.
  • a diethylzinc solution in toluene (concentration: 15% by weight, 5.3 g, 6.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -20°C.
  • Chloroiodomethane (2.26 g, 12.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -10 to -15°C for 10 minutes, and then cooled to -20°C.
  • a diethylzinc solution in toluene (concentration: 15% by weight, 9.4 g, 11.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -15°C.
  • Chloroiodomethane (4.02 g, 22.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept at -15°C. After completion of the dropwise addition, the mixture was stirred at -10 to -15°C for 20 minutes, and then cooled to -25°C.
  • a diethylzinc solution in toluene (concentration: 15% by weight, 6.92 g, 8.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -25°C.
  • Chloroiodomethane (2.96 g, 16.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -20 and -25°C. After completion of the dropwise addition, the mixture was stirred at -10 to -20°C for 15 minutes, and then cooled to -25°C.
  • a diethylzinc solution in toluene (concentration: 15% by weight, 9.4 g, 0.0114 mol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -15°C.
  • Chloroiodomethane (4.02 g, 22.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -10 to -15°C for 20 minutes, and then cooled to -25°C.
  • a diethylzinc solution in toluene (concentration: 15% by weight, 6.92 g, 8.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -20°C.
  • Chloroiodomethane (2.96 g, 16.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -5 to -15°C for 10 minutes, and then cooled to -25°C.
  • a diethylzinc solution in toluene (concentration: 15% by weight, 5.4 g, 0.0066 mol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -20°C.
  • Chloroiodomethane (2.33 g, 13.2 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -5 to -15°C for 20 minutes, and then cooled to -25°C.
  • methyl magnesium bromide (0.97 mol/L tetrahydrofuran solution, 3.0 ml, 2.9 mmol) was placed into a 30-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer.
  • 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]acetalde hyde (a diastereomer mixture with a component ratio of 1:2, 0.20 g, 0.99 mmol) and tetrahydrofuran (1 ml) were placed, and added dropwise in 5 minutes, with the temperature kept at 20°C. At the same temperature, the mixture was stirred for 30 minutes.
  • Flavor and/or fragrance compositions for perfume were prepared according to the formulation shown in Table 4 below by using the compounds synthesized in Examples 1, 2, 4, 8, 9, and 10 described above.
  • Table 4 Formulation Parts by weight Amyl cinnamic aldehyde 50 Benzyl acetate 50 1-Citronellol 3 Citronellol 100 Dihydromyrcenol 30 Dimethyl phenylethyl carbinol 50 Hexyl cinnamic aldehyde 100 Indole 2 Linalool 100 Phenylacetaldehyde dimethyl acetal 10 Phenylethyl alcohol 150 SANTALEX T® (manufactured by Takasago International Corporation) 25 Terpineol 30 Compound of Example 1, 2, 4, 8, 9, or 10 300 Total 1000
  • Flavor and/or fragrance compositions for perfume were prepared according to the formulation shown in Table 5 below by using the compounds of Examples 1, 2, 4, 8, 9, and 10.
  • Formulation Parts by weight CALONE® (manufactured by Firmenich) 10 Canthoxal 10 ⁇ -Decalactone 30 ⁇ -Dihydroionone 50 Eugenol 5 HEDIONE® (manufactured by Firmenich) 250 HELIOBOUQUET® (manufactured by Takasago International Corporation) 40 cis-3-Hexenyl salicylate 15 1-Citronellol 40 Linalool 50 1-Muscone (manufactured by Takasago International Corporation) 40 MUSK T® (manufactured by Takasago International Corporation) 200 ORBITONE® (manufactured by Takasago International Corporation) 150 THESARON® (manufactured by Takasago International Corporation) 10 Compound of Example 1, 2, 4, 8, 9, or 10 100 Total 1000

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  • Seasonings (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)
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Description

    Technical Field
  • The present invention relates to a flavor and/or fragrance composition containing a compound having a cyclopropane ring.
    • Background Art
  • Some compounds having a cyclopropane ring are known to be useful as raw materials for flavor compositions and/or fragrance compositions. For example, [1-methyl-2-(5-methyl-4-hexen-2-yl)cyclopropyl]methanol has an odor similar to those of citrus and 3-methyl-5-phenyl-1-pentanol, with rosy floral note ( WO 2012/160189 A1 ). Meanwhile, 1-methyl-2-[(2,2,3-trimethylcyclopentyl)methyl]cyclopropyl] methanol has a natural sandalwood-like odor ( US 2010/0069508 A1 ). In addition, 2-(1-phenylethyl)cyclopropylmethanol are known as compounds having a cyclopropane ring and a benzene ring, but their odors are not mentioned (Synthesis (1999), No. 6, 1063-1075).
  • In J. Cossy et al., Synthesis of Isopropenylcyclopropanes - Revision of the Relative Configuration of Cyclopropyl Ketones Obtained by 1,3-Elimintaion of γ-Epoxy Ketones, Eur. J. Org. Chem. 2001, pages 339 - 348 efficient stereoselective routes towards isoprenylcyclopropanes are described. Secondary cis-isopropenylcyclopropylcarbinols have been obtained either by regio- and stereoselective hydroxyl-directed cyclopropanation of the corresponding dienols or from bicyclic cyclopropyl lactones derived from intramolecular cyclopropanation of allylic diazoacetates. Furthermore, it has been shown that base-induced 1,3-elimination of γ-epoxy ketones afford trans-2-(hydroxymethyl)cyclopropyl ketones, and the reactivity of these compounds has been reinvestigated.
  • In J Cossy et al., Directing effect of a neighboring Aromatic Group in the Cyclopropanation of Allylic Alcohols, J. Org. Chem. 1998, 63, pages 5728 - 5729 it was shown that the cyclopropanation of chiral acyclic allylic alcohols bearing a stereocenter at the remote allylic position can proceed with synthetically useful levels of stereoselectivity. When an aryl group was present at this stereocenter, a reversal of selectivity has been observed between Sm- and Zn-promoted cyclopropanation reactions, which has been interpreted by a π-metal interaction resulting in a net directing effect of this substituent in the second case.
  • WO 2008/052379 A2 describes 2,2,3-trimethylcyclopentane derivatives of the following formula (1):
    Figure imgb0001
  • In formula (1), R1 is methyl or ethyl, and R2 is hydrogen, methyl or ethyl. WO 2008/052379 A2 furthermore relates to a method of the production of compounds of formula (1) and to fragrance compositions comprising same.
    • Summary of the Invention
  • With the recent diversification of products such as various cosmetics, health and sanitary articles, and pharmaceuticals, development of a flavor and/or fragrance substance having high diffusibility, unique odor quality, highly preferred characteristics, long lasting, good stability, and high safety as a flavor and/or fragrance for them has been demanded more eagerly than before. Especially, regarding flavor and/or fragrance materials having a floral or citrus-like odor, only an insufficient number of compounds satisfy such requirements, and besides the conventionally known substances, development of a novel material satisfying the above-described characteristics has been awaited.
  • Accordingly, an object of the present invention is to provide a compound capable of imparting a floral or citrus-like odor satisfying the above-described requirements.
  • Under such circumstances, the present inventor has conducted intensive study, and consequently has found that a compound obtained by subjecting an allyl alcohol derivative to cyclopropane formation has a strong floral or citrus-like odor, and can serve as a useful odor-imparting agent. This finding has led to the completion of the present invention. Specifically, the present invention includes the following contents [1] to [7].
    1. [1] A compound represented by Formula (1):
      Figure imgb0002
      • wherein R1 and R3 are both methyl groups, R2 and R5 each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,
      • R4 represents a group selected from a hydroxymethyl group, a 1-hydroxy-1-ethyl group, a 1-hydroxy-1-propyl group, a 1-hydroxy-1-butyl group, and a 2-hydroxy-1-propyl group;
      • m is 0 to 2;
      • n is 0 or 1; and
      the wavy lines indicate a cis-configuration, a trans-configuration, or a mixture of a cis-configuration and a trans-configuration with respect to position-2 on the cyclopropane ring.
    2. [2] The compound according to the above-described [2], wherein
      R1, R2, and R3 are all methyl groups.
    3. [3] The compound according to the above-described [2] to [4], wherein
      R5 is a methyl group.
    4. [4] A flavor and/or fragrance composition, comprising: at least one of the compounds according to the above-described [1] to [3].
    5. [5] A food or beverage, a cosmetic, a daily necessity or grocery, an oral cavity composition, a hair-care product, a skin-care product, a body-cleaning agent, a laundry detergent, a laundry softener, a toiletry product, a fiber or fiber product, a garment, or a pharmaceutical, comprising the flavor and/or fragrance composition according to the above-described [4].
  • The compound of the present invention is a very useful flavor and/or fragrance material which is highly preferred, is also excellent in odor-imparting characteristics, and is excellent in diffusibility and long lasting. By blending such a compound of the present invention, an agent for imparting a highly preferred odor can be provided.
    • Description of Embodiments
  • A compound of the present invention is represented by Formula (1):
    Figure imgb0003
  • In Formula (1), R1 and R3 are both methyl groups, R2 and R5 each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. The alkyl group having 1 to 3 carbon atoms is, for example, a methyl group. R4 represents a group selected from a hydroxymethyl group, a 1-hydroxy-1-ethyl group, a 1-hydroxy-1-propyl group, a 1-hydroxy-1-butyl group, and a 2-hydroxy-1-propyl group. R4 is, for example, selected from a hydroxymethyl group, and a 1-hydroxy-1-ethyl group. m is 0 to 2, and, for example, 0 or 1. n is 0 or 1. The wavy lines indicate a cis-configuration, a trans-configuration, or a mixture of a cis-configuration and a trans-configuration with respect to position-2 on the cyclopropane ring.
  • A compound of Formula (1), where n is 0, and R4 is a hydroxymethyl group, is synthesized, for example, by a method shown below.
    Figure imgb0004
  • First, an allyl alcohol derivative (3) is reacted with a carbenoid prepared from diethylzinc and chloroiodomethane to synthesize a compound (4) having a cyclopropane ring. The compound (4) having a cyclopropane ring is obtained as a mixture of diastereomers having the relative configurations shown below, and the odor threshold of (4b) is lower than that of (4a).
    Figure imgb0005
  • A compound of Formula (1), where n is 0, m is 0, R1 and R3 are methyl groups, and R4 is a 1-hydroxy-1-ethyl group, is synthesized, for example, by a method shown below.
    Figure imgb0006
  • First, a compound (5) having a cyclopropane ring is oxidized to obtain an aldehyde compound (6), which is then subjected to a Grignard reaction. Thus, a compound (7) can be synthesized. Reactions usable as a method for the oxidation include the TEMPO oxidation, the Uemura Oxidation, the Albright-Goldman oxidation, the Mukaiyama oxidation, the Ley-Griffith oxidation, the Swern oxidation. The compound (7) having a cyclopropane ring is obtained as a mixture of isomers having relative configurations shown below. The odor threshold of (R*)-1-[(1S*,2S*)-1-methyl-2-((R*)-1-phenylethyl)cyclopropyl ]ethanol (7a) is 100 times or more lower than that of (S*)-1-[(1S*,2S*)-1-methyl-2-((R*)-1-phenylethyl)cyclopropyl ]ethanol (7b).
    Figure imgb0007
  • A compound having a cyclopropane ring of Formula (1), where n is 1, m is 0, R1 and R3 are methyl groups, and R4 is a formyl group, is synthesized, for example, by a method shown below.
    Figure imgb0008
  • First, a compound (6) is subjected to the Wittig reaction to synthesize an enol ether (8). The obtained enol ether is hydrolyzed in the presence of an acid catalyst. Thus, a compound (9) having a cyclopropane ring can be easily synthesized. Acids used here include acetic acid, citric acid, hydrochloric acid, sulfuric acid.
  • If necessary, the thus obtained compound of the present invention can be isolated and purified. Examples of methods for the isolation and purification include column chromatography, vacuum distillation, crystallization. These methods can be carried out alone or in combination.
  • The amount of the compound represented by Formula (1) blended in a flavor and/or fragrance composition is not particularly limited, and is preferably 0.01 to 60% by weight, and particularly preferably 0.1 to 40% by weight, relative to the flavor and/or fragrance composition.
  • In addition, any commonly used blended flavor and/or fragrance can be blended in the flavor and/or fragrance composition of the present invention. The thus obtained flavor and/or fragrance composition can impart a fresh and highly preferred odor. Moreover, the flavor and/or fragrance composition of the present invention can be blended, as an odor component, in foods and beverages, cosmetics, air-fresheners, daily necessities and groceries, oral cavity compositions, hair-care products, skin-care products, body-cleaning agents, laundry detergents, laundry softeners, toiletry products, fibers and fiber products, garments, pharmaceuticals. Specifically, the flavor and/or fragrance composition of the present invention can be blended in shampoos, rinses, perfumes, colognes, hair tonics, hair creams, pomades, base materials for other hair cosmetics, soaps, dish washing detergents, laundry detergents, softeners, sterilizing detergents, deodorant detergents, room air-fresheners, disinfectants, pesticides, bleaching agents, other various health and sanitary detergents, dentifrices, mouthwashes, toilet papers, odor-imparting agents for facilitating ingestion of pharmaceuticals, in amounts generally employed in these industrial fields. In this manner, its unique odor can be imparted to these products, and the values of the products can be enhanced.
    • Examples
  • Hereinafter, the present invention will be described in detail by way of Examples. However, the present invention is not limited to these examples at all. Note that, in Examples, the values of physical properties were measured by using the following instruments and devices.
  • NMR was measured by using DRX500 manufactured by Bruker. CDCl3 was used as the solvent, and the chemical shifts were referenced to TMS and expressed in ppm. The coupling constants J were expressed in Hz.
  • GC/MS was measured by using an HP 6890 GC system and an HP5973MS detector of Agirent Technologies. The column used was InertCap 1 (manufactured by GL Sciences Inc., 30 m in length×0.25 mm in inner diameter, liquid-phase film thickness: 0.25 µm). The injection port temperature was 250°C, and the detector temperature was 250°C. The conditions of the temperature rise were as follows: 100°C(15°C/minute)300°C.
  • The GC purity was measured by using a 7890A GC system of Agirent Technologies. The column used was InertCap 1 (manufactured by GL Sciences Inc., 20 m in length×0.18 in mm inner diameter, liquid-phase film thickness: 0.18 µm). The injection port temperature was 250°C, and the detector temperature was 250°C. The conditions of the temperature rise were as follows: 100°C(15°C/minute)230°C.
    • (Example 1) Synthesis of 1-Methyl-2-(1-phenylethyl)cyclopropylmethanol
  • Figure imgb0009
  • Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 37.9 g, 46.0 mmol) was placed into a 200-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -20°C. Chloroiodomethane (16.22 g, 92.0 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 to -20°C. After completion of the dropwise addition, the mixture was stirred at -10 to -15°C for 30 minutes, and then cooled to -25°C. (E)-2-Methyl-4-phenylpent-2-ene-1-ol (4.11 g, 23.3 mmol) was added dropwise over a period of 60 minutes in the range from-20 to -25°C. After completion of the dropwise addition, the stirring was continued at -15 to -25°C for 60 minutes. Next, a 20% aqueous sulfuric acid solution (17.0 ml) was added. After stirring for 10 minutes, the aqueous layer was separated. The organic layer was washed twice with water (20 ml), and the solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate =8:2). [(1R*,2S*)-1-Methyl-2-((R*)-1-phenylethyl) cyclopropyl]methan ol (1.85 g, 9.74 mmol, 42% yield) was obtained as the main isomer, and
    [(1R*,2S*)-1-methyl-2-((S*)-1-phenylethyl)cyclopropyl]methan ol (0.55 g, 2.9 mmol, 12% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
    Main isomer
    GC/MS (m/e):
    190 (M+,<1), 172 (1), 159 (7), 146 (9), 131 (17), 118 (80), 117 (100), 106 (60), 105 (80), 91 (45), 77 (20)
    1H (500 MHz, CDCl3) :
    7.31 (ddm, J=8.3, 7.1, 2H), 7.27 (dm, J=8.3, 2H), 7.20 (tm, J=7.1, 1H), 3.41 (d, J=11.0, 1H), 3.35 (d, J=11.0, 1H), 2.31 (dq, J=10.6, 7.0, 1H), 1.34 (d, J=7.0, 3H), 1.28 (s, 3H), 0.87 (ddd, J=10.6, 8.8, 5.7, 1H), 0.52 (dd, J=8.8, 4.9, 1H), 0.12 (dd, J=5.7, 4.9, 1H)
    13C (125 MHz, CDCl3)
    147.2(s), 128.3(d), 126.0(d), 126.0(d), 72.4(t), 39.8(d), 29.7(d), 23.6(s), 22.6(q), 16.6(t), 15.3(q)
    Minor Isomer
    GC/MS (m/e):
    190 (M+, <1), 172 (1), 159 (7), 146 (5), 131 (17), 118 (80), 117 (100), 106 (60), 105 (80), 91 (45), 77 (20)
    1H (500 MHz, CDCl3) :
    7.29 (ddm, J=8.3, 7.1, 2H), 7.26 (dm, J=8.3, 2H), 7.18 (tm, J=7.1, 1H), 3.33 (d, J=10.4, 1H), 3.27 (d, J=10.4, 1H), 2.34 (dq, J=10.5, 7.0, 1H), 1.35 (d, J=7.0, 3H), 1.06 (s, 3H), 0.97 (ddd, J=10.5, 8.9, 5.5, 1H), 0.70 (dd, J=8.9, 4.7, 1H), 0.18 (dd, J=5.5, 4.7, 1H)
    13C (125 MHz, CDCl3)
    147.7(s), 128.4(d), 126.6(d), 125.9(d), 72.2(t), 40.0(d), 29.2(d), 23.4(s), 23.3(q), 16.5(t), 15.7(q)
    • (Example 2) Synthesis of 1-Methyl-2-(1-phenylethyl)cyclopropylmethanol
  • Figure imgb0010
  • Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 69.8 g, 84.8 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -20°C. Chloroiodomethane (29.9 g, 169.6 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -10 to -15°C for 30 minutes, and then cooled to -25°C. (Z)-2-Methyl-4-phenylpent-2-ene-1-ol (7.59 g, 42.4 mmol) was added dropwise over a period of 60 minutes in the range from -20 to -25°C. After completion of the dropwise addition, the stirring was continued at -15 to -25°C for 60 minutes. Next, a 20% aqueous sulfuric acid solution (31.3 ml) was added. After stirring for 10 minutes, the aqueous layer was separated. The organic layer was washed twice with water (30 ml), and the solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate =8:2). [(1S*,2S*)-1-Methyl-2-((R*)-1-phenylethyl)cyclopropyl]methan ol (4.93 g, 25.9mmol, 61% yield) was obtained as the main isomer, and
    [(1S*,2S*)-1-methyl-2-((S*)-1-phenylethyl)cyclopropyl]methan ol (0.61 g, 3.2 mmol, yield 7.5%) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
    Main Isomer
    GC/MS (m/e):
    172 (M+-H2O, 1), 157 (5), 146 (20), 131 (27), 118 (72), 117 (100), 106 (65), 105 (75), 91 (53), 77 (25)
    1H (500 MHz, CDCl3) :
    7.30 (ddm, J=7.9, 7.2, 2H), 7.25 (dm, J=7.9, 2H), 7.19 (tm, J=7.2, 1H), 3.70 (m, 2H), 2.35 (dq, J=10.6, 7.0, 1H), 1.38 (d, J=7.0, 3H), 1.30 (m, OH), 1.21 (s, 3H), 0.94 (ddd, J=10.6, 8.4, 5.9, 1H), 0.45 (dd, J=8.4, 4.8, 1H), 0.21 (dd, J=5.9, 4.8, 1H) 13C (125 MHz, CDCl3)
    147.3(s), 128.3(d), 126.9(d), 125.9(d), 67.1(t), 40.0(d), 33.3(d), 23.5(s), 23.0(q), 22.9(q), 17.3(t)
    Minor Isomer
    GC/MS (m/e):
    190 (M+, <1), 172 (4), 157 (10), 143 (7), 131 (17), 118 (72), 117 (100), 106 (65), 105 (67), 91 (44), 77 (20)
    1H (500 MHz, CDCl3) :
    7.32 (ddm, J=8.3, 7.1, 2H), 7.28 (dm, J=8.3, 2H), 7.21 (tm, J=7.1, 1H), 3.52 (dd, J=11.6, 9.1, 1H), 3.33 (d, J=11.6, 1H), 2.34 (dq, J=10. 6, 6.9, 1H), 1.34 (d, J=6. 9, 3H), 1.13 (s, 3H), 1.06 (ddd, J=10.6, 8.3, 5.5, 1H), 0.66 (dd, J=8.3, 4.6, 1H), 0.40 (m, OH), 0.27 (dd, J=5.5, 4.6, 1H)
    13C (125 MHz, CDCl3)
    147.7(s), 128.8(d), 126.4(d), 126.4(d), 67.3(t), 40.9(d), 31.9(d), 24.1(q), 23.1(s), 22.6(q), 17.8(t)
    • (Example 3) Synthesis of (1S*,2S*)-1-Methyl-2-[(R*)-1-phenylethyl]cyclopropane carbaldehyde
  • Figure imgb0011
  • Under a nitrogen atmosphere, [(1S*,2S*)-1-methyl-2-((R*)-1-phenylethyl)cyclopropyl]methan ol (1.02 g, 5.37 mmol), potassium bromide (0.36 g), 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (0.085 g), and toluene (10 ml) were placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to 0°C. An aqueous sodium hypochlorite solution (concentration: approximately 13.5%, 5.0 g, 9.1 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept at 0°C. After completion of the dropwise addition, the temperature was raised to 18°C over a period of 60 minutes. After that, the aqueous layer was separated, and the organic layer was washed with a 10% aqueous sodium thiosulfate solution and with water. The solvent was recovered under reduced pressure to obtain a condensed residue, (1S*,2S*)-1-methyl-2-[(R*)-1-phenylethyl]cyclopropane carbaldehyde (0.91 g, 4.8 mmol, 89% yield).
    GC/MS (m/e):
    188 (M+, 5), 159 (7), 141 (5), 128 (20), 118 (82), 117 (100), 115 (45), 105 (43), 91 (60), 83 (60), 77 (44)
    1H (500 MHz, CDCl3) :
    9.37 (s, 1H), 7.34 (ddm, J=8.3, 7.2, 2H), 7.28 (dm, J=8.3, 2H), 7.24 (tm, J=7.2, 1H), 2.71 (dq, J=10.4, 7.0, 1H), 1.51-1.42 (m, 2H), 1.32 (s, 3H), 1.30 (d, J=7.0, 3H), 1.09 (dd, J=7.5, 4.6, 1H)
    13C (125 MHz, CDCl3)
    202.7(d), 145.6(s), 128.5(d), 126.7(d), 126.5(d), 40.1(d), 38.8(d), 32.9(s), 22.5(t), 21.9(q), 18.4(q)
    • (Example 4) Synthesis of 1-[(1S*,2S*)-1-Methyl-2-((R*)-1-phenylethyl)cyclopropyl]etha nol
  • Figure imgb0012
  • Under a nitrogen atmosphere, methyl magnesium bromide (0.97 mol/L, tetrahydrofuran solution, 8.5 ml, 8.25 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -10°C. (1S*,2S*)-1-Methyl-2-[(R*)-1-phenylethyl]cyclopropane carbaldehyde (1.03 g, 5.5 mmol) was placed into the dropping funnel, and added dropwise in 5 minutes with the temperature kept at -10°C. After stirring for 60 minutes, a 20% aqueous sulfuric acid solution (4.5 g) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). (R*)-1-[(1S*,2S*)-1-Methyl-2-((R*)-1-phenylethyl)cyclopropyl ]ethanol (0.75 g, 3.68 mmol, 67% yield) was obtained as the main isomer, and (S*)-1-[(1S*,2S*)-1-methyl-2-((R*)-1-phenylethyl)cyclopropyl ]ethanol (0.205 g, 1.0 mmol, 18% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
    Main Isomer
    GC/MS (m/e):
    186 (M+-H2O, 1), 171 (6), 160 (15), 145 (7), 131 (29), 118 (87), 117 (100), 106 (68), 105 (86), 91 (53), 77 (26), 72 (30), 70 (30)
    1H (500 MHz, CDCl3) :
    7.29 (ddm, J=8.3, 7.2, 2H), 7.24 (dm, J=8.3, 2H), 7.19 (tm, J=7.2, 1H), 3.60 (q, J=6.4, 1H), 2.46 (dq, J=10.4, 6.9, 1H), 1.46 (d, J=6.9, 3H), 1.31 (d, 6.4, 3H), 1.09 (s, 3H), 0.92 (ddd, J=10.4, 8.5, 5.9, 1H), 0.41 (dd, J=8.5, 4.9, 1H), 0.01 (dd, J=5.9, 4.9, 1H)
    13C (125 MHz, CDCl3)
    147.7(s), 128.3(d), 127.0(d), 125.9(d), 70.5(d), 39.0(d), 34.5(d), 26.5(s), 23.6(q), 20.5(q), 18.4(q), 17.5(t)
    Minor Isomer
    GC/MS (m/e):
    186 (M+-H2O, 1), 171 (7), 160 (13), 145 (7), 131 (32), 118 (85), 117 (100), 106 (65), 105 (84), 91 (55), 77 (27), 72 (21), 70 (29)
    1H (500 MHz, CDCl3) :
    7.30 (ddm, J=8.3, 7.2, 2H), 7.21 (dm, J=8.3, 2H), 7.19 (tm, J=7.2, 1H), 3.58 (q, J=6.4, 1H), 2.39 (dq, J=10.5, 6.9, 1H), 1.37 (d, J=6.4, 3H), 1.36 (d, 6.9, 3H), 1.09 (s, 3H), 0.95 (ddd, J=10.5, 8.6, 5.7, 1H), 0.46 (dd, J=8.6, 4.6, 1H), 0.19 (dd, J=5.7, 4.6, 1H)
    13C (125 MHz, CDCl3)
    147.5 (s), 128.3 (d), 126.9(d), 126.0(d), 70.8(d), 39.1(d), 34.1(d), 27.5(s), 23.6(q), 20.4(q), 18.9(t), 18.7(q)
    • (Example 5) Synthesis of 1,2-Dimethyl-2-(1-phenylethyl)cyclopropylmethanol
  • Figure imgb0013
  • Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 10.9 g, 13.2 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -15°C. Chloroiodomethane (4.68 g, 26.5 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -15°C for 30 minutes. (Z)-2,3-Dimethyl-4-phenylpent-2-ene-1-ol (1.26 g, 6.63 mmol) was added dropwise at -10 to -15°C over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at 12°C for 60 minutes. Next, a 20% aqueous sulfuric acid solution (4.8 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1,2-Dimethyl-2-((S*)-1-phenylethyl)cyclopropyl]me thanol (0.47 g, 2.3 mmol, 35% yield) was obtained as the main isomer, and [(1S*,2S*)-1,2-dimethyl-2-((R*)-1-phenylethyl)cyclopropyl]me thanol (0.45 g, 2.2 mmol, 33% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
    Main Isomer
    GC/MS (m/e):
    204 (M+, <1), 186 (3), 171 (25), 149 (45), 132 (39), 131 (79), 117 (86), 115 (36), 106 (44), 105 (100), 99 (37), 91 (60), 77 (31)
    1H (500 MHz, CDCl3) :
    7.32-7.27 (m, 4H), 7.20 (m, 1H), 3.78 (m, 2H), 2.68 (q, 7.2, 1H), 1.36 (d, J=7.2, 3H), 1.35 (OH), 1.25 (s, 3H), 0.92 (s, 3H), 0.73 (d, J=4.8, 1H), 0.22 (d, J=4.8, 1H)
    13C (125 MHz, CDCl3)
    145.1(s), 128.0(d), 127.9(d), 125.9(d), 68.2(t), 42.3(d), 30.2(s), 26.7(s), 25.5(t), 18.3(q), 16.8(q), 14.7(q)
    Minor Isomer
    GC/MS (m/e):
    204 (M+, <1), 186 (3), 171 (24), 149 (44), 132 (46), 131 (89), 117 (94), 115 (38), 106 (48), 105 (100), 99 (38), 91 (65), 77 (35)
    1H (500 MHz, CDCl3) :
    7.32 (ddm, J=7.8, 7.0, 2H), 7.28 (dm, J=7.8, 2H), 7.19 (tm, J=7.0, 1H), 3.64 (m, 2H), 2.64 (q, 7.1, 1H), 1.40 (d, J=7.1, 3H), 1.24 (s, 3H), 1.08 (s, 3H), 0.90 (t, J=6.7, OH), 0.45 (d, J=4.6, 1H), 0.29 (d, J=4.6, 1H)
    13C (125 MHz, CDCl3)
    145.3(s), 128.4(d), 127.5(d), 126.0(d), 68.3(t), 42.5(d), 29.3(s), 28.5(s), 25.1(t), 18.9(q), 18.2(q), 15.6(q)
    • (Example 6) Synthesis of 1-Methyl-2-(1-(4-methylphenyl)ethyl)cyclopropylmethanol
  • Figure imgb0014
  • Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 5.3 g, 6.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -20°C. Chloroiodomethane (2.26 g, 12.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -10 to -15°C for 10 minutes, and then cooled to -20°C. At the same temperature, (E)-2-methyl-4-(4-methylphenyl)pent-2-en-1-ol (0.60 g, 3.2 mmol) was added dropwise over a period of 10 minutes. After completion of the dropwise addition, the stirring was continued at -15 to -25°C for 60 minutes. Next, a 20% aqueous sulfuric acid solution (2.5 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1R*,2S*)-1-Methyl-2-((R*)-1-(4-methylphenyl)ethyl) cyclopro pyl]methanol (0.24 g, 1.18 mmol, 36% yield) was obtained as the main isomer, and [(1R*,2S*)-1-methyl-2-((S*)-1-(4-methylphenyl)ethyl) cyclopro pyl]methanol (0.013 g, 0.064 mmol, 2% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
    Main Isomer
    GC/MS (m/e):
    186 (M+-H2O, 2), 173 (13), 160 (13), 149 (19), 145 (23), 132 (80), 131 (64), 120 (62), 119 (88), 117 (100), 115 (48), 105 (40), 91 (62), 77 (21)
    1H (500 MHz, CDCl3) :
    7.16 (dm, J=8.2, 2H), 7.12 (dm, J=8.2, 2H), 3.41 (d, J=11.0, 1H), 3.35 (d, J=11.0, 1H), 2.33 (s, 3H), 2.27 (dq, J=10.6, 7.0, 1H), 1.32 (d, J=7.0, 3H), 1.28 (s, 3H), 0.84 (ddd, J=10.6, 8.8, 5.7, 1H), 0.52 (dd, J=8.8, 4.8, 1H), 0.11 (dd, J=5.7, 4.8, 1H) 13C (125 MHz, CDCl3)
    144.2(s), 135.4(s), 129.0(d), 126.8(d), 72.5(t), 39.4(d), 29.9(d), 23.6(s), 22.7(q), 21.0(q), 16.6(t), 15.3(q)
    Minor Isomer
    GC/MS (m/e):
    204 (M+, <1), 186 (7), 173 (16), 157 (8), 149 (23), 145 (20), 132 (98), 131 (84), 120 (66), 119 (100), 117 (96), 115 (53), 105 (42), 91 (64), 77 (24)
    1H (500 MHz, CDCl3) :
    7.14 (dm, J=8.2, 2H), 7.10 (dm, J=8.2, 2H), 3.34 (d, J=10.8, 1H), 3.27 (d, J=10. 8, 1H), 2.32 (s, 3H), 2.31 (dq, J=10.6, 7.0, 1H), 1.33 (d, J=7.0, 3H), 1.06 (s, 3H), 0.95 (ddd, J=10.6, 8.9, 5.6, 1H), 0.68 (dd, J=8.9, 4.7, 1H), 0.18 (dd, J=5.6, 4.7, 1H) 13C (125 MHz, CDCl3)
    144.6(s), 135.2(s), 129.1(d), 126.4(d), 72.3(t), 39.6(d), 29.3(d), 23.36(q), 23.35(s), 20.9(q), 16.5(t), 15.7(q)
    • (Example 7) Synthesis of 1-Methyl-2-(1-(4-methylphenyl)ethyl)cyclopropylmethanol
  • Figure imgb0015
  • Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 9.4 g, 11.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -15°C. Chloroiodomethane (4.02 g, 22.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept at -15°C. After completion of the dropwise addition, the mixture was stirred at -10 to -15°C for 20 minutes, and then cooled to -25°C. (Z)-2-Methyl-4-(4-methylphenyl)pent-2-en-1-ol (1.08 g, 5.7 mmol) was added dropwise at -20 to -25°C over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at -15 to -25°C for 60 minutes. Next, a 20% aqueous sulfuric acid solution (4.2 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1-Methyl-2-((R*)-1-(4-methylphenyl)ethyl) cyclopro pyl]methanol (0.79 g, 3.8 mmol, 68% yield) was obtained as the main isomer, and [(1S*,2S*)-1-methyl-2-((S*)-1-(4-methylphenyl)ethyl) cyclopro pyl]methanol (0.21 g, 1.0 mmol, 18% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
    Main Isomer
    GC/MS (m/e):
    186 (M+-H2O, 1), 173 (9), 171 (7), 160 (18), 149 (16), 145 (25), 132 (76), 131 (66), 120 (65), 119 (82), 117 (100), 115 (47), 105 (46), 91 (56), 77 (19)
    1H (500 MHz, CDCl3) :
    7.14 (dm, J=8.3, 2H), 7.12 (dm, J=8.3, 2H), 3.71 (d, J=11.3, 1H), 3.69 (d, J=11.3, 1H), 2.32 (s, 3H), 2.32 (dq, J=10.6, 6.9, 1H), 1.36 (d, J=6.9, 3H), 1.29 (br.s, OH), 1.20 (s, 3H), 0.92 (ddd, J=10.6, 8.4, 5.8, 1H), 0.44 (dd, J=8.4, 4.8, 1H), 0.20 (dd, J=5.8, 4.8, 1H)
    13C (125 MHz, CDCl3)
    144.3 (s), 135.4(s), 129.0(d), 126.7(d), 67.1(t), 39.6(d), 33.4(d), 23.5(s), 23.1(q), 22.9(q), 21.0(q), 17.3(t)
    Minor Isomer
    GC/MS (m/e):
    186 (M+-H2O, 9), 173 (11), 171 (15), 157 (10), 149 (19), 145 (20), 132 (91), 131 (90), 120 (70), 119 (95), 117 (100), 115 (54), 105 (43), 91 (66), 77 (23)
    1H (500 MHz, CDCl3) :
    7.17 (dm, J=8.2, 2H), 7.13 (dm, J=8.2, 2H), 3.54 (dd, J=12.6, 9.7, 1H), 3.33 (dd, J=12.6, 1.2, 1H), 2.31 (s, 3H), 2.30 (dq, J=10.6, 6.9, 1H), 1.32 (d, J=6.9, 3H), 1.13 (s, 3H), 1.03 (ddd, J=10.6, 8.3, 5.4, 1H), 0.64 (dd, J=8.3, 4.6, 1H), 0.39 (br.d, J=9, 7, OH), 0.25 (dd, J=5.4, 4.6, 1H)
    13C (125 MHz, CDCl3)
    144.7(s), 135.9(s), 129.5(d), 126.3(d), 67.4(t), 40.5(d), 32.0(d), 24.2(q), 23.1(s), 22.6(q), 21.0(q), 17.9(t)
    • (Example 8) Synthesis of 1-Methyl-2-(1-(3-methylphenyl)ethyl)cyclopropylmethanol
  • Figure imgb0016
  • Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 6.92 g, 8.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -25°C. Chloroiodomethane (2.96 g, 16.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -20 and -25°C. After completion of the dropwise addition, the mixture was stirred at -10 to -20°C for 15 minutes, and then cooled to -25°C. At the same temperature, (E)-2-methyl-4-(3-methylphenyl)pent-2-en-1-ol (0.80 g, 4.2 mmol) was added dropwise over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at -10 to -25°C for 20 minutes. Next, a 20% aqueous sulfuric acid solution (3.1 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1R*,2S*)-1-Methyl-2-((R*)-1-(3-methylphenyl)ethyl) cyclopro pyl]methanol (0.38 g, 1.9 mmol, 45% yield) was obtained as the main isomer, and [(1R*,2S*)-1-methyl-2-((S*)-1-(3-methylphenyl)ethyl) cyclopro pyl]methanol (0.014 g, 0.069 mmol, yield 1.6%) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
    Main Isomer
    GC/MS (m/e):
    186 (M+-H2O, 1), 173 (16), 160 (15), 145 (30), 132 (81), 131 (66), 120 (73), 119 (81), 117 (100), 115 (46), 105 (36), 91 (49), 77 (16)
    1H (500 MHz, CDCl3) :
    7.19 (dd, J=8.0, 7.4, 1H), 7.07 (br.s, 1H), 7.06 (dm, 8.0, 1H), 7.02 (dm, 7.4, 1H), 3.42 (d, J=11.0, 1H), 3.36 (d, J=11.0, 1H), 2.35 (s, 3H), 2.26 (dq, J=10.6, 7.0, 1H), 1.33 (d, J=7.0, 3H), 1.28 (s, 3H), 0.86 (ddd, J=10.6, 8.8, 5.7, 1H), 0.52 (dd, J=8.8, 4.8, 1H), 0.12 (dd, J=5.7, 4.8, 1H)
    13C (125 MHz, CDCl3)
    147.2(s), 137.8(s), 128.2(d), 127.7(d), 126.7(d), 124.0(d), 72.4(t), 39.7(d), 29.7(d), 23.6(s), 22.7(q), 21.5(q), 16.6(t), 15.3(q)
    Minor Isomer
    GC/MS (m/e):
    204 (M+, <1), 186 (4), 173 (17), 157 (10), 149 (11), 145 (21), 132 (93), 131 (80), 120 (79), 119 (88), 117 (100), 115 (54), 105 (42), 91 (71), 77 (26)
    1H (500 MHz, CDCl3) :
    7.18 (ddm, J=8.4, 7.4, 1H), 7.06 (br.s, 1H), 7.05 (dm, 8.4, 1H),
    6.99 (dm, 7.4, 1H), 3.33 (d, J=10.9, 1H), 3.27 (d, J=10.9, 1H), 2.33 (s, 3H), 2.30 (dq, J=10.5, 7.0, 1H), 1.34 (d, J=7.0, 3H), 1.09 (br.s, OH), 1.06 (s, 3H), 0.96 (ddd, J=10.5, 8.9, 5.5, 1H), 0.68 (dd, J=8.9, 4.7, 1H), 0.17 (dd, J=5.5, 4.7, 1H)
    13C (125 MHz, CDCl3)
    147.6(s), 137.8(s), 128.3(d), 127.4(d), 126.6(d), 123.6(d), 72.2(t), 39.9(d), 29.2(d), 23.34(s), 23.28(q), 21.5(q), 16.5(t), 15.7(q)
    • (Example 9) Synthesis of 1-methyl-2-(1-(3-methylphenyl)ethyl)cyclopropylmethanol
  • Figure imgb0017
  • Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 9.4 g, 0.0114 mol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -15°C. Chloroiodomethane (4.02 g, 22.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -10 to -15°C for 20 minutes, and then cooled to -25°C. (Z)-2-Methyl-4-(3-methylphenyl)pent-2-en-1-ol (1.09 g, 5.7 mmol) was added dropwise at -20 to -25°C over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at -15 to -25°C for 40 minutes. Next, a 20% aqueous sulfuric acid solution (4.2 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1-Methyl-2-((R*)-1-(3-methylphenyl)ethyl) cyclopro pyl]methanol (0.83 g, 4.1 mmol, 70% yield) was obtained as the main isomer, and [(1S*,2S*)-1-methyl-2-((S*)-1-(3-methylphenyl)ethyl) cyclopro pyl]methanol (0.20 g, 0.99 mmol, 17% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
    Main Isomer
    GC/MS (m/e):
    186 (M+-H2O, 1), 171 (7), 160 (20), 145 (30), 132 (66), 131 (65), 120 (69), 119 (71), 117 (100), 115 (50), 105 (46), 91 (62), 77 (21)
    1H (500 MHz, CDCl3) :
    7.19 (dt, J=0.9, 7.4, 1H), 7.05 (s, 1H), 7.04 (dm, J=7.4, 1H), 7.01 (dm, J=7.4, 1H), 3.71 (d, J=11.3, 1H), 3.68 (d, J=11.3, 1H), 2.34 (s, 3H), 2.32 (dq, J=10.6, 7.0, 1H), 1.36 (d, J=7.0, 3H), 1.31 (br.s, OH), 1.20 (s, 3H), 0.93 (ddd, J=10.6, 8.4, 5.8, 1H), 0.44 (dd, J=8.4, 4.8, 1H), 0.21 (dd, J=5.8, 4.8, 1H) 13C (125 MHz, CDCl3)
    147.3(s), 137.8(s), 128.2(d), 127.7(d), 126.7(d), 123.9(d), 67.1(t), 40.0(d), 33.3(d), 23.5(s), 23.1(q), 22.9(q), 21.5(q), 17.3(t)
    Minor Isomer
    GC/MS (m/e):
    186 (M+-H2O, 7), 171 (18), 157 (11), 145 (22), 132 (81), 131 (95), 120 (77), 119 (83), 117 (100), 115 (63), 105 (45), 91 (76), 77 (25)
    1H (500 MHz, CDCl3) :
    7.21 (dd, J=8, 7, 1H), 7.08 (dm, J=7, 1H), 7.07 (m, 1H), 7.02 (dm, J=8, 1H), 3.53 (dd, J=11.7, 10.0, 1H), 3.34 (dd, J=11.7, 2.8, 1H), 2.34 (s, 3H), 2.30 (dq, J=10.6, 6.9, 1H), 1.33 (d, J=6. 9, 3H), 1.13 (s, 3H), 1.04 (ddd, J=10. 6, 8.3, 5.4, 1H), 0. 64 (dd, J=8.3, 4.6, 1H), 0.42 (dd, J=10.0, 2.8, OH), 0.26 (dd, J=5.4, 4.6, 1H)
    13C (125 MHz, CDCl3)
    147.7(s), 138.4(s), 128.7(d), 127.3(d), 127.2(d), 123.4(d), 67.4(t), 40.8(d), 31.9(d), 24.1(q), 23.1(s), 22.6(q), 21.5(q), 17.9(t)
    • (Example 10) Synthesis of 1-Methyl-2-(1-(2-methylphenyl)ethyl)cyclopropylmethanol
  • Figure imgb0018
  • Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 6.92 g, 8.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -20°C. Chloroiodomethane (2.96 g, 16.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -5 to -15°C for 10 minutes, and then cooled to -25°C. (E)-2-Methyl-4-(2-methylphenyl)pent-2-en-1-ol (0.80 g, 4.2 mmol) was added dropwise at -20 to -25°C over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at -15 to -25°C for 60 minutes. Next, a 20% aqueous sulfuric acid solution (3.1 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1R*,2S*)-1-Methyl-2-((R*)-1-(2-methylphenyl) ethyl) cyclopro pyl]methanol (0.32 g, 1.6 mmol, 37% yield) was obtained as the main isomer, and [(1R*,2S*)-1-methyl-2-((S*)-1-(2-methylphenyl)ethyl) cyclopro pyl]methanol (0.025 g, 0.12 mmol, 3% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
    Main Isomer
    GC/MS (m/e):
    204 (M+, <1), 186 (5), 171 (13), 157 (10), 149 (10), 145 (15), 143 (20), 132 (64), 131 (63), 120 (74), 119 (87), 117 (100), 115 (53), 105 (35), 91 (56), 77 (18)
    1H (500 MHz, CDCl3) :
    7.36 (dd, J=7.7, 1.0, 1H), 7.19 (tm, J=7.7, 1H), 7.13 (dm, J=7.7, 1H), 7.09 (dt, J=1.4, 7.7, 1H), 3.45 (d, J=11.0, 1H), 3.38 (d, J=11.0, 1H), 2.62 (dq, J=10.5, 6.9, 1H), 2.31 (s, 3H), 1.30 (s, 3H), 1.27 (d, J=6. 9, 3H), 0.99 (ddd, J=10.5, 8.9, 5.8, 1H), 0.51 (dd, J=8.9, 4.9, 1H), 0.02 (dd, J=5.8, 4.9, 1H)
    13C (125 MHz, CDCl3)
    145.6(s), 134.7(s), 130.2(d), 126.2(d), 126.1(d), 125.6(d), 72.5(t), 34.6(d), 29.1(d), 23.6(s), 22.9(q), 19.6(q), 16.5(t), 15.5(q)
    Minor Isomer
    GC/MS (m/e):
    186 (M+-H2O, 6), 173 (17), 171 (15), 157 (14), 149 (17), 143 (25), 132 (62), 131 (70), 129 (30), 128 (40), 120 (52), 119 (72), 117 (100), 115 (66), 105 (32), 91 (60), 77 (23) 1H (500 MHz, CDCl3) :
    7.33 (dd, J=7.5, 0.8, 1H), 7.19 (dt, J=2.0, 7.5, 1H), 7.11 (dm, J=7.5, 1H), 7.08 (dt, J=1.4, 7.5, 1H), 3.35 (d, J=10.8, 1H), 3.31 (d, J=10.8, 1H), 2.48 (dq, J=10.4, 6.9, 1H), 2.29 (s, 3H), 1.27 (d, J=6.9, 3H), 1.15 (ddd, J=10.4, 8.8, 5.4, 1H), 1.09 (br.s), 0.90 (s, 3H), 0.74 (dd, J=8.8, 4.6, 1H), 0.22 (dd, J=5.4, 4.6, 1H)
    13C (125 MHz, CDCl3)
    146.2(s), 134.4(s), 130.2(d), 126.3(d), 125.6(d), 125.2(d), 72.2(t), 36.3(d), 28.5(d), 23.0(s), 22.9(q), 19.2(q), 17.3(t), 15.5(q)
    • (Example 11) Synthesis of 1-Methyl-2-(1-(2-methylphenyl)ethyl)cyclopropylmethanol
  • Figure imgb0019
  • Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 5.4 g, 0.0066 mol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -20°C. Chloroiodomethane (2.33 g, 13.2 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between -15 and -20°C. After completion of the dropwise addition, the mixture was stirred at -5 to -15°C for 20 minutes, and then cooled to -25°C. (Z)-2-Methyl-4-(2-methylphenyl)pent-2-en-1-ol (0.62 g, 3.3 mmol) was added dropwise at -20 to -25°C over a period of 15 minutes. After completion of the dropwise addition, the stirring was continued at -15 to -25°C for 20 minutes. Next, a 20% aqueous sulfuric acid solution (2.5 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1-Methyl-2-((R*)-1-(2-methylphenyl) ethyl) cyclopro pyl]methanol (0.47 g, 2.3 mmol, 70% yield) was obtained as the main isomer, and [(1S*,2S*)-1-methyl-2-((S*)-1-(2-methylphenyl)ethyl)cyclopro pyl]methanol (0.12 g, 0.59 mmol, 17% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
    Main Isomer
    GC/MS (m/e):
    186 (M+-H2O, <1), 173 (4), 171 (6), 160 (8), 149 (9), 145 (18), 143 (15), 132 (55), 131 (62), 120 (76), 119 (77), 117 (100), 115 (56), 105 (38), 91 (59), 77 (19)
    1H (500 MHz, CDCl3):
    7.35 (dd, J=7, 1.1, 1H), 7.19 (dt, J=1.8, 7, 1H), 7.12 (dd, J=7, 1.8, 1H), 7.08 (dt, J=1.3, 7, 1H), 3.725 (d, J=11.5, 1H), 3.715 (d, J=11.5, 1H), 2.67 (dq, J=10.5, 6.9, 1H), 2.29 (s, 3H), 1.32 (d, J=6.9, 3H), 1.23 (s, 3H), 1.06 (ddd, J=10.5, 8.4, 5.9, 1H), 0.43 (dd, J=8.4, 4.8, 1H), 0.11 (dd, J=5.9, 4.8, 1H)
    13C (125 MHz, CDCl3)
    145.8(s), 134.7(s), 130.2(d), 126.2(d), 126.1(d), 125.6(d), 67.3(t), 34.8(d), 32.6(d), 23.5(s), 23.2(q), 23.0(q), 19.6(q), 17.1(t)
    Minor Isomer
    GC/MS (m/e):
    186 (M+-H2O, 2), 173 (12), 171 (8), 157 (8), 149 (14), 145 (14), 143 (17), 132 (69), 131 (73), 120 (64), 119 (67), 117 (100), 115 (64), 105 (36), 91 (73), 77 (22)
    1H (500 MHz, CDCl3):
    7.41 (dd, J=7, 0.9, 1H), 7.22 (dt, J=2.2, 7, 1H), 7.13 (dm, J=7, 1H), 7.11 (dt, J=1.3, 7, 1H), 3.47 (dd, J=11.7, 9, 1H), 3.17 (d, J=11.7, 1H), 2.52 (dq, J=10.4, 6.8, 1H), 2.30 (s, 3H), 1.28 (d, J=6.8, 3H), 1.18 (ddd, J=10.4, 8.2, 5.4, 1H), 1.15 (s, 3H), 0.70 (dd, J=8.2, 4.2, 1H), 0.29 (dd, J=5.4, 4.2, 1H), 0.17 (br.d, J=9, OH)
    13C (125 MHz, CDCl3)
    145.8(s), 134.6(s), 130.6(d), 126.7(d), 126.2(d), 125.4(d), 67.6(t), 37.0(d), 31.5(d), 22.91(s), 22.88(q), 22.5(q), 19.1(q), 18.6(t)
    • (Example 12) Synthesis of 2-[(1R*,2S*)-1-Methyl-2-(1-phenylethyl)cyclopropyl]acetalde hyde
  • Figure imgb0020
  • Under a nitrogen atmosphere, (methoxymethyl)triphenylphosphonium chloride (5.0 g, 14.6 mmol) and tetrahydrofuran (20 ml) were placed into a 200-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to -40°C. A solution of potassium t-butoxide (1.63 g, 14.5 mmol) in tetrahydrofuran (10 ml) was placed into the dropping funnel, and added dropwise with the temperature kept between -35 and -40°C. After completion of the dropwise addition, the mixture was stirred at the same temperature for 5 minutes, and then (1S*,2S*)-1-methyl-2-(1-phenylethyl) cyclopropane carbaldehyde (1.5 g, 8.0 mmol, a diastereomer mixture with a component ratio of 1:2) was added dropwise over a period of 5 minutes. After completion of the dropwise addition, the temperature was raised to -20°C, and the stirring was continued for 2 hours. Next, a saturated aqueous ammonium chloride solution (20 ml) and hexane (30 ml) were added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure. The precipitated white solid was filtered to obtain the residue. Next, under a nitrogen atmosphere, the residue (1.33 g) obtained as above, acetonitrile (6 ml), and a 5% aqueous sulfuric acid solution (2 ml) were placed into a 100-ml flask equipped with a stirring apparatus, a reflux tube, and a thermometer, and starred at 55°C for 1 hour. After that, toluene (10 ml) was added, the aqueous layer was separated, and the organic layer was washed with water. The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate =8:2) to obtain 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]acetalde hyde (a diastereomer mixture, 0.56 g, 2.8 mmol, 35% yield).
    Main Isomer
    GC/MS (m/e):
    202 (M+, <1), 187(<1), 169 (1), 158 (9), 143 (14), 128 (11), 118 (100), 117 (85), 105 (90), 97 (56), 91 (36), 77 (22)
    Minor Isomer
    GC/MS (m/e):
    202 (M+, <1), 187 (<1), 169 (1), 158 (9), 143 (16), 128 (11), 118 (99), 117 (76), 105 (100), 97 (51), 91 (39), 77 (23) 13C (125 MHz, CDCl3): data of mixture
    203.5(d), 203.1(d), 146.9(s), 146.8(s), 128.5(d), 128.4(d), 126.9(d), 126.6(d), 126.1(d), 48.0(t), 47.9(t), 41.4(d), 40.6(d), 31.7(d), 30.6(d), 25.5(q), 25.2(q), 23.8(q), 22.5(q), 18.6(t), 18.3(t), 17.1(s), 16.7(s)
    • (Example 13) Synthesis of 2-[(1R*,2S*)-1-Methyl-2-(1-phenylethyl)cyclopropyl]ethanol
  • Figure imgb0021
  • Under a nitrogen atmosphere, 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]acetalde hyde (a diastereomer mixture with a component ratio of 1:2, 0.20 g, 0.99 mmol), cyclopentyl methyl ether (4 ml), and sodium borohydride (0.05 g, 1.3 mmol) were placed into a 30-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and methanol (0.05 g) was added with stirring at 20°C, followed by stirring at the same temperature for 60 minutes. Next, a 5% aqueous sulfuric acid solution (1.3 g) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (2 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane: ethyl acetate =8:2) to obtain 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]ethanol (a diastereomer mixture with a component ratio of 1:2, 0.19 g, 0.93 mmol, 94% yield).
    Main Isomer
    GC/MS (m/e):
    204 (M+, <1), 189 (<1), 171 (1), 159 (7), 143 (6), 131 (23), 118 (100), 117 (51), 105 (87), 91 (28), 77 (15)
    Minor Isomer
    GC/MS (m/e):
    204 (M+, <1), 189 (<1), 171 (2), 159 (10), 143 (8), 131 (27), 118 (92), 117 (47), 105 (100), 91 (30), 77 (16)
    13C (125 MHz, CDCl3): data of mixture
    147.7(s), 147.5(s), 128.29(d), 128.26(d), 126.9(d), 126.7(d), 125.9(d), 125.8(d), 61.7(t), 61.5(t), 40.5(d), 40.1(d), 36.6(t), 36.4(t), 32.6(d), 31.3(d), 25.1(q), 24.7(q), 23.8(q), 22.6(q), 18.5(t), 18.33(t), 18.30(s), 18.0(s)
    • (Example 14) Synthesis of 1-[(1R*,2S*)-1-Methyl-2-(1-phenylethyl)cyclopropyl]propan-2 -ol
  • Figure imgb0022
  • Under a nitrogen atmosphere, methyl magnesium bromide (0.97 mol/L tetrahydrofuran solution, 3.0 ml, 2.9 mmol) was placed into a 30-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer. In the dropping funnel, 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]acetalde hyde (a diastereomer mixture with a component ratio of 1:2, 0.20 g, 0.99 mmol) and tetrahydrofuran (1 ml) were placed, and added dropwise in 5 minutes, with the temperature kept at 20°C. At the same temperature, the mixture was stirred for 30 minutes. Next, a 5% aqueous sulfuric acid solution (2.9 g) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (2 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. The results of a GC analysis showed that the condensed residue was a mixture of four isomers. This residue was purified by silica gel column chromatography (hexane: ethyl acetate =8:2). Thus, a component (0.016 g, 0.07 mmol, 7% yield) with the longest retention time in the GC analysis was obtained. Results of evaluation based on gas chromatography-olfactometry (GC-O) showed that this component was a component having the lowest odor threshold, among the 4 isomers.
    GC/MS (m/e):
    218 (M+, <1), 200 (1), 185 (3), 171 (4), 157 (8), 143 (16), 131 (13), 118 (100), 117 (50), 105 (90), 91 (35), 77 (14), 69 (18) 1H (500 MHz, CDCl3):
    7.29 (ddm, J=7.5, 7.2, 2H), 7.25 (dm, J=7.5, 2H), 7.19 (tm, J=7.2, 1H), 4.09 (m, 1H), 2.29 (dq, J=10.5, 6.9, 1H), 2.03 (ddd, J=13.6, 5.9, 1.3, 1H), 1.42 (br.s, OH), 1.33 (d, J=6.9, 3H), 1.28 (d, 6.2, 3H), 1.27 (dd, J=13.6, 7.7, 1H), 1.11 (s, 3H), 0.71 (ddd, J=10.5, 8.6, 5.8, 1H), 0.44 (ddd, J=8.6, 4.7, 1.3, 1H), 0.01 (dd, J=5.8, 4.7, 1H)
    13C (125 MHz, CDCl3)
    147.6(s), 128.3(d), 127.0(d), 125.8(d), 67.6(d), 42.7(t), 40.0(d), 32.9(d), 25.7(q), 23.5(q), 22.5(q), 18.95(s), 18.90(t)
    • (Example 15) Synthesis of 2-[(1S*,2S*)-1-Methyl-2-((R*)1-phenylethyl)cyclopropyl]ethan ol
  • Figure imgb0023
  • (1R*,2S*)-1-Methyl-2-[(R*)-1-phenylethyl]cyclopropane carbaldehyde was obtained by changing the raw material in the above-described method of Example 3 to 2-[(1R*,2S*)-1-methyl-2-((R*)1-phenylethyl)cyclopropyl]metha nol (2.04 g, 10.7 mmol), and carrying out the same method as in Example 3. Subsequently, 2-[(1S*,2S*)-1-methyl-2-((R*)1-phenylethyl)cyclopropyl]aceta ldehyde (1.26 g, 6.2 mmol) was obtained by the same method as in Example 12 described above. Moreover, 2-[(1S*,2S*)-1-methyl-2-((R*)1-phenylethyl)cyclopropyl]ethan ol (1.21 g, 5.9 mmol) was obtained by the same method as in Example 13 described above. The total yield was 55%.
    GC/MS (m/e):
    204 (M+, <1), 189 (<1), 171 (1), 159 (8), 143 (7), 131 (22), 118 (100), 117 (52), 105 (87), 91 (28), 77 (15),
    1H (500 MHz, CDCl3):
    7.30 (ddm, J=8.3, 7.1, 2H), 7.26 (dm, J=8.3, 2H), 7.19 (tm, J=7.1, 1H), 3.80 (m, 2H), 2.28 (dq, J=10.7.0, 1H), 1.68 (ddd, J=13.8, 7.6, 6.5, 1H), 1.42 (ddd, J=,13.8, 7.7, 6.7, 1H), 1.34 (d, J=7.0, 3H), 1.27 (m, OH), 1.20 (s, 3H), 0.78 (ddd, J=10.6, 8.7, 5.7, 1H), 0.45 (dd, J=8.7, 4.7, 1H), 0.06 (dd, J=5.7, 4.7, 1H) 13C (125 MHz, CDCl3) 147.4(s), 128.3(d), 126.9(d), 125.9(d), 61.4(t), 44.2(t), 40.1(d), 31.4(d), 22.6(q), 19.0(t), 18.1(s), 17.5(q)
    • (Evaluation of Odor Quality)
  • The compounds synthesized in Examples 1 to 15 described above were evaluated for the quality of their odors. The results are shown in the following Tables 1 to 3 separately according to the odor quality. [Table 1]
    Structural formula Quality of odor
    Exampl e 1
    Figure imgb0024
         		Floral, Rose, Muguet, 3-Methyl-5-phenyl-1-pentano 1 like, Strong
    Exampl e 6
    Figure imgb0025
         		Floral, Rose, Muguet
    Exampl e 8
    Figure imgb0026
         		Floral, Rose, Muguet, Strong
    Exampl e 10
    Figure imgb0027
         		Floral, Rose, Muguet
    Exampl e 15
    Figure imgb0028
         		Floral, Rose, Muguet
    [Table 2]
    Structural formula Odor quality
    Example 2
    Figure imgb0029
         		Citrus, Rhubarb, Woody, Strong
    Example 4
    Figure imgb0030
         		Citrus, Rhubarb, Animal, Strong
    Example 5
    Figure imgb0031
         		Citrus, Rhubarb, Strong
    Example 7
    Figure imgb0032
         		Citrus, Rhubarb
    Example 9
    Figure imgb0033
         		Citrus, Rhubarb, Strong
    Example 11
    Figure imgb0034
         		Citrus, Rhubarb, Strong
    Example 13 Isomer with long GC retention
    Figure imgb0035
         		Citrus, Rhubarb
    time
    Example 14
    Figure imgb0036
         		Citrus, Rhubarb
    [Table 3]
    Structural formula Odor quality
    Example 3
    Figure imgb0037
         		Aldehyde-like, Floral, Citrus
    Example 12
    Figure imgb0038
         		Aldehyde-like, Floral, Citrus, weak
    • (Example 16: Flavor and/or Fragrance Composition with Muguet Note)
  • Flavor and/or fragrance compositions for perfume were prepared according to the formulation shown in Table 4 below by using the compounds synthesized in Examples 1, 2, 4, 8, 9, and 10 described above. [Table 4]
    Formulation Parts by weight
    Amyl cinnamic aldehyde 50
    Benzyl acetate 50
    1-Citronellol 3
    Citronellol 100
    Dihydromyrcenol 30
    Dimethyl phenylethyl carbinol 50
    Hexyl cinnamic aldehyde 100
    Indole 2
    Linalool 100
    Phenylacetaldehyde dimethyl acetal 10
    Phenylethyl alcohol 150
    SANTALEX T® (manufactured by Takasago International Corporation) 25
    Terpineol 30
    Compound of Example 1, 2, 4, 8, 9, or 10 300
    Total 1000
  • Results of sensory evaluation conducted by four professional panelists with five or more years experience were as follows. Specifically, all the panelists stated that the flavor and/or fragrance compositions with muguet note containing the compounds of Examples 1, 2, 4, 8, 9, and 10 had strong floral odors, and also had excellent diffusibility.
    • (Example 17: Flavor and/or Fragrance Compositions with Marine Note)
  • Flavor and/or fragrance compositions for perfume were prepared according to the formulation shown in Table 5 below by using the compounds of Examples 1, 2, 4, 8, 9, and 10. [Table 5]
    Formulation Parts by weight
    CALONE® (manufactured by Firmenich) 10
    Canthoxal 10
    γ-Decalactone 30
    β-Dihydroionone 50
    Eugenol 5
    HEDIONE® (manufactured by Firmenich) 250
    HELIOBOUQUET® (manufactured by Takasago International Corporation) 40
    cis-3-Hexenyl salicylate 15
    1-Citronellol 40
    Linalool 50
    1-Muscone (manufactured by Takasago International Corporation) 40
    MUSK T® (manufactured by Takasago International Corporation) 200
    ORBITONE® (manufactured by Takasago International Corporation) 150
    THESARON® (manufactured by Takasago International Corporation) 10
    Compound of Example 1, 2, 4, 8, 9, or 10 100
    Total 1000
  • Results of sensory evaluation conducted by four professional panelists with five or more years experience were as follows. Specifically, all the panelists stated that the flavor and/or fragrance compositions with marine note containing the compounds of Examples 1, 2, 4, 8, 9, and 10 had distinct marine and ozone notes, and also had excellent diffusibility.
    • (Example 18: Shampoo)
  • Shampoos (100 g) each scented with 1.0% of one of the flavor and/or fragrance compositions of Examples 16 and Example 17 were prepared according to the formulation shown in Table 6 below. [Table 6]
    Formulation (components) Blended amount (g)
    Sodium polyoxyethylene lauryl ether sulfate 14.00
    Lauramidopropyl betaine 4.00
    Coconut oil fatty acid diethanol amide 3.00
    Cationic cellulose 0.50
    Ethylene glycol distearate 1.00
    ethyl paraoxybenzoate 0.25
    Citric acid Quantum Sufficient
    Flavor and/or fragrance composition of Example 16 or 17 1.00
    Purified water the Balance
    Total 100.00

Claims (8)

  1. A compound represented by Formula (1):
    Figure imgb0039
     wherein
    R1 and R3 are both methyl groups, R2 and R5 each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
    R4 represents a group selected from a hydroxymethyl group, a 1-hydroxy-1-ethyl group, a 1-hydroxy-1-propyl group, a 1-hydroxy-1-butyl group, and a 2-hydroxy-1-propyl group;
    m is 0 to 2;
    n is 0 or 1; and
    the wavy lines indicate a cis-configuration, a trans-configuration, or a mixture of a cis-configuration and a trans-configuration with respect to position-2 on the cyclopropane ring.
  2. The compound according to claim 1, wherein
    R1, R2, and R3 are all methyl groups.
  3. The compound according to any one of claims 1 or 2, wherein
    R5 is a methyl group.
  4. A flavor and/or fragrance composition, comprising the compound according to any one of claims 1 to 3.
  5. A food or beverage, a cosmetic, a daily necessity or grocery, a toiletry product, a fiber or fiber product, or a pharmaceutical, comprising the flavor and/or fragrance composition according to claim 4.
  6. The daily necessity according to claim 5, which is a laundry detergent or a laundry softener.
  7. The toiletry product according to claim 5, which is an oral cavity composition, a hair-care product, a skin-care product or a body-cleaning agent.
  8. The fiber product according to claim 5, which is a garment.
EP14765462.8A 2013-03-12 2014-03-07 Compound having cyclopropane ring, and flavor and/or fragance composition containing same Active EP2985273B1 (en)

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Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3862340A (en) 1972-08-25 1975-01-21 Int Flavors & Fragrances Inc Flavoring with 5-phenyl pentenals
US3948973A (en) * 1972-08-29 1976-04-06 Sterling Drug Inc. Halocyclopropyl substituted phenoxyalkanoic acids
JPS63183522A (en) 1986-09-08 1988-07-28 Kuraray Co Ltd Perfume composition
JPH0710793B2 (en) 1987-03-17 1995-02-08 株式会社クラレ Method for producing primary allyl ester
US20050119156A1 (en) 2001-12-19 2005-06-02 Luca Turin Aromachemicals
ES2274985T3 (en) 2001-12-19 2007-06-01 Flexitral, Inc. IMPROVED CHEMICALS.
GB0621805D0 (en) * 2006-11-03 2006-12-13 Givaudan Sa Organic compounds
GB0716232D0 (en) * 2007-08-21 2007-09-26 Givaudan Sa Cyclopropanation process
CN102300550B (en) * 2008-12-01 2014-04-23 宝洁公司 Perfume systems
ES2429423T3 (en) 2009-11-02 2013-11-14 Firmenich S.A. Smelling substances with aniseed notes
WO2012159223A1 (en) 2011-05-25 2012-11-29 Givaudan Sa Trimethyloctadienol and derivatives thereof used as fragrance ingredient

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Title
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EP2985273A1 (en) 2016-02-17
EP2985273A4 (en) 2016-07-13
US9296675B2 (en) 2016-03-29
WO2014142025A1 (en) 2014-09-18

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